Relationship between lipoprotein(a) and whole blood reducing viscosity: A cross-sectional study

Lipoprotein(a) [Lp(a)] has been confirmed as a causal risk factor of atherosclerotic cardiovascular disease, but its role on circulation is not completely clear and is still being explored. Therefore, this study attempts to explore the relationship between Lp(a) and whole blood reducing viscosity (WBRV), to better understand the role of Lp(a) in circulatory and cardiovascular diseases. We retrospectively analyzed the data of consecutive subjects in the physical examination center of the Affiliated Hospital of Ningbo University Medical College from January 2022 to May 2022. Pearson or spearman correlation analysis was used to test the statistical relationship between 2 continuous variables according to whether they are normal; 131 participants were retrospectively enrolled in this study. The low-density lipoprotein concentration was associated with whole blood viscosity at low-shear (R = 0.220, P = .012), middle-shear (R = 0.226, P = .01), and high-shear viscosity (R = 0.212, P = .015), as well as plasma viscosity (RS = 0.207, P = .018). Lp(a) was not associated with whole blood viscosity at low, middle, and high shear rates, but was associated with WBRV at low shear (RS = 0.204, P = .019) and middle shear rates (RS = 0.197, P = .024). Lp(a) is associated with high WBRV, which may impart more insights into the role of Lp(a) in cardiovascular disease.


Introduction
[3] Blood viscosity (BV) is also considered to be related to atherosclerosis and microvascular function. [4,5]Contrary to expectation, many studies have shown that there is no correlation between Lp(a) and BV or plasma viscosity. [6,7]However, the correlation between Lp(a) and whole blood reduced viscosity has not been concerned.In this study, we explored the relationship between Lp(a) and reduced BV.

Study population
From January 2022 to May 2022, consecutive patients who completed physical examination in the Physical examination Center of the First Affiliated Hospital of Ningbo University were retrospectively reviewed.Inclusion criteria: Patients' physical examination items included BV and Lp(a).Patients with incomplete data were excluded.The studies involving human participants were reviewed and approved by medical ethics committee of Affiliated Hospital of Medical College of Ningbo University.Written informed consent for participation was waived for this study by medical ethics committee of Affiliated Hospital of Medical College of Ningbo University due to the retrospective nature of the study.The formulation of this study scheme was in accordance with the requirements of the Declaration of Helsinki of the World Medical Association.

Methods
Weight and height were measured using a standardized approach, followed by the calculation of body mass index in kg/ Patient consent was waived due to the study's retrospective nature.

The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.
The study was conducted in accordance with the Declaration of Helsinki and approved by the Medical Ethics Committee of the First Affiliated Hospital of Ningbo University.a The First Affiliated Hospital of Ningbo University, Ningbo, China.
Jing and Zhu • Medicine (2023) 102:48 Medicine m 2 .Venous blood was collected after overnight fasting (>8 h).BV was measured using an automated blood rheology analyzer (ZONCI Technology Co., Ltd., Beijing, China).BV levels at 5 s −1 are reported as low-shear viscosity, BV measurements at 30 s −1 are reported as middle-shear viscosity, and BV measurements at 200 s −1 are reported as high-shear viscosity.For plasma viscosity the average of measurements at shear rates of 200 s −1 was calculated.
Whole blood reductive viscosity (WBRV) refers to the whole BV value when the hematocrit (HCT) is 1, also known as the unit HCT viscosity, or is defined as the contribution of the unit HCT to the relative viscosity of the whole blood.
Whole blood reduction viscosity was calculated by the following formula: WBV-PV is the increase of viscosity in plasma due to the addition of human blood cells, so (WBV-PV)/PV is the increase rate of viscosity increase to original viscosity.The higher of the ratio, the greater the influence of red blood cells on BV.The volume of red blood cells in the whole blood reflects the concentration of red blood cells, and its volume percentage is generally called HCT.The ratio divided by HCT is converted into the influence of unit HCT on BV.According to the formula, the whole blood reduced high shear viscosity, whole blood reduced middle shear viscosity, and whole blood reduced low shear viscosity can be calculated.Obviously, WBRV is a dimensionless value without units.

Statistical analysis
All statistical analyses were performed using SPSS 26.0 for Mac (IBM Corp., Armonk, NY) and GraphPad Prism version 9.0 for Mac (GraphPad Software, San Diego, CA).Data were checked for normality with the Kolmogorov-Smirnov test and shown as mean ± SD or median [P25-P75] depending on the distribution.Categorical variables are displayed as percentages and absolute numbers.Select Pearson or spearman correlation analysis to test the statistical relationship between 2 continuous variables according to whether they are normal.Level of significance was set at P < .05.

Results
Overall, 131 participants were enrolled in this study.Table 1 shows the characteristics of the examined population.The mean age was 64 years, mean body mass index was 25.32 kg/m 2 , and 81% were men.Lp(a) ranged from 15 to 773 mmol/L.

Discussion
In this cross-sectional analysis, we report that LDL concentrations are associated with higher WBV measured at low-shear, middle-shear, and high-shear rates.In comparison to the lack of association between Lp(a) and WBV, concentrations of Lp(a) were associated with WBRV at low-shear and middle-shear rates.
It has long been believed that the main physiological determinants of whole blood rheology tend to be the HCT and the fibrinogen concentration.Many recent studies have shown that lipid levels are important for hemorheology. [8]Specifically, the increase of high-density lipoprotein is related to the decrease of BV, while the increase of LDL and triglyceride leads to the opposite phenomenon. [9]In a prior cross-sectional study, patients with type IIa hyperlipoproteinemia, a positive correlation was shown between LDL concentrations and plasma viscosity (P < .01). [10]Another study showed that, compared to normolipidemic subjects, the PV (P = .007)and WBV (P = .013) of hyperlipidemic subjects were higher, and it was also found that PV was directly associated with LDL cholesterol in simple correlation analysis. [7,11]BV depends on HCT and is a function of HCT.WBRV is defined as the influence of unit HCT on BV.In this study, we found the correlation between Lp(a) and reducing viscosity, not viscosity.Lp(a) is a LDL cholesterol-like particle bound to apolipoprotein(a) and has been confirmed as a causal risk factor of atherosclerotic cardiovascular disease by genome-wide association, epidemiology, and clinical studies. [12]In addition, there is an increasing body of evidence identifying Lp(a) as a strong, independent, and potentially causal risk factor for calcific aortic valve stenosis. [13,14]To our knowledge, this is the first study that explores the relationship between WBRV and Lp(a).
Our study had several limitations.First, it is a cross-sectional study and cannot make a causal analysis.Second, data such as fibrinogen that will affect BV have not obtained due to the retrospective nature; the results may be biased.Third, due to the inclusion of a physical examination population and the retrospective nature, we were unable to obtain patient medication history and other risk factors.

Conclusion
Lp(a) is associated with high WBRV, which may impart more insights into the role of Lp(a) in cardiovascular disease.

Table 1
Characteristics of the study participants.

Table 2
Association between blood viscosity and lipids (P values)*.